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Access Type

WSU Access

Date of Award

January 2019

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Cancer Biology

First Advisor

Yubin . Ge

Abstract

Acute Myeloid Leukemia (AML) is a frustratingly difficult to treat disease (67% 5 year survival for children and 24% for adults). The standard of care, similar to outcomes, has seen few improvements over the last several decades. The Bcl-2 family, which controls cell survival and apoptosis, is dysregulated in AML. Bcl-2, which is overexpressed in AML and associated with chemoresistance, is a promising therapeutic target. The now FDA approved venetoclax (ABT-199) is a BH3 mimetic that is able to bind to anti-apoptotic Bcl-2 and prevent it from sequestering pro-apoptotic Bim. While overall response rates are promising, our lab and others had found that resistance often occurs through anti-apoptotic Mcl-1 sequestering Bim and preventing apoptosis.

In this dissertation, we used the molecular tool and Mcl-1 inhibitor A-1210477 and found that inhibition of Mcl-1 can synergize with venetoclax to induce apoptosis in AML cells. To inhibit Mcl-1 in a more clinically relevant manner, we sought to target Mcl-1 transcription or protein stability using clinically available drugs. XPO1 is overexpressed in AML cells and its inhibition decreases Mcl-1 levels and shows anti-leukemic activity. XPO1 inhibition by KPT-330 (selinexor) or KPT-8602 (eltanexor) was able to synergistically enhance apoptosis induced by venetoclax. XPO1 inhibition decreased Mcl-1 by decreasing protein half-life but not transcript levels. XPO1 inhibition and venetoclax were able to disrupt Bim binding to both Bcl-2 and Mcl-1.

CDK9 inhibition transcriptionally decreases levels of Mcl-1 and c-Myc, and shows anti-leukemic activity. CDK9 inhibition by flavopiridol or voruciclib decreases Mcl-1 transcripts in a transient manner. CDK9 inhibition was able to disrupt Bim binding to Mcl-1 alone and in combination with venetoclax. The efficacy of the combination was dependent upon downregulation of Mcl-1 and c-Myc. Interrupted dosing of CDK9 inhibition was effective in vitro and in vivo.

Overall, Mcl-1 inhibition is a valid strategy to overcome resistance to venetoclax in AML. This strategy has been validated through direct targeting of Mcl-1 and clinically relevant indirect targeting of transcript levels or protein stability of Mcl-1 to decrease Mcl-1 protein levels.

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